Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear oncogenes v-erbA and v-ets are known to cooperate with other viral oncogenes in the induction of avian erythroleukemia. Thus, in the case of avian erythroblastosis virus (AEV), v-erbA enhances the effect of the tyrosine kinase-encoding v-erbB oncogene by blocking the terminal differentiation of erythroid cells. In the case of E26 virus a fusion of the product from v-ets to that of the nuclear oncogene v-myb is a prerequisite for leukemogenicity. Here we show that an artificial virus carrying both v-erbA and v-ets induces a rapid, acute erythroleukemia phenotypically similar to that induced by AEV. In contrast, virus constructs containing either v-erbA or v-ets alone are non-leukemogenic, although they are capable of transforming erythroid cells in vitro. Analysis of in vitro-transformed cells showed that v-erbA induces a block of differentiation without abrogating dependence on anemic serum, while v-ets predominantly causes anemic serum independence. As expected, cells transformed by both oncogenes exhibit an increased proliferative potential, are blocked in differentiation and are anemic serum independent. These data demonstrate that two separately expressed nuclear oncoproteins can complement each other in vitro and in vivo. They also show that the v-Ets protein on its own can contribute to leukemogenesis.
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PMID:The nuclear oncogenes v-erbA and v-ets cooperate in the induction of avian erythroleukemia. 134 19

The avian retrovirus oncogene v-ski was analysed for its ability to alter the differentiation program of erythroid cells and to cooperate with tyrosine kinase oncogenes in leukemogenesis. For this, a retrovirus combining v-ski with a temperature-sensitive version of the v-sea oncogene was constructed. In transformed erythroblasts, v-ski disturbed the concerted expression of several erythrocyte genes, leading to an abnormal erythroblast phenotype. Expression levels of hemoglobin and erythrocyte anion transporter (band 3) were elevated, while expression of the erythroid-specific histone H5 was strongly suppressed. v-ski could also be shown to repress or severely retard the temperature-induced erythroid differentiation of v-ski/ts-v-sea-transformed cells. The undifferentiated cells had an abnormal erythroblast or early reticulocyte phenotype characterized by unusually low levels of histone H5. In chicks, the v-ski/ts-v-sea virus displayed enhanced leukemogenicity compared with viruses containing just the single oncogenes. Thus, v-ski cooperates with tyrosine kinase oncogenes in a similar fashion to the v-erbA oncogene, however the pattern of genes affected by these two oncogenes is different.
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PMID:The v-ski oncogene cooperates with the v-sea oncogene in erythroid transformation by blocking erythroid differentiation. 140 32

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.
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PMID:[Activation of protooncogenes by point mutations in hematological malignancies]. 151 54

A non-leukemogenic version of the v-myb oncogene causes in vitro transformation of avian myeloblasts, which are dependent on chicken myelomonocytic growth factor (cMGF). We have shown that this version of v-myb, when combined with the erythroleukemia-inducing v-erbB oncogene, is capable of causing a mixed myeloid and erythroid leukemia. Myeloid leukemic cells transformed by this construct produce cMGF. To test whether autocrine growth stimulation via cMGF is the essential contribution of the tyrosine kinase oncogene v-erbB in avian myeloid leukemogenesis we constructed another retrovirus containing both the non-leukemogenic v-myb and the cMGF cDNA. This virus induced myeloid leukemia at high efficiency. In a third construct we combined v-myb with the human EGF-receptor gene. Myeloid cells transformed by this construct could be stimulated to grow by the addition of cMGF or EGF. Growth stimulation with EGF was blocked by a cMGF antiserum indicating that activation of a normal tyrosine kinase-type receptor induces cMGF expression but does not bypass the cMGF requirement. We conclude that cMGF plays a key role in the growth regulation of normal and transformed avian myeloid cells.
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PMID:Activation of cMGF expression is a critical step in avian myeloid leukemogenesis. 167 38

Chronic myelogenous leukemia and one type of acute lymphoblastic leukemia are characterized by a 9;22 chronosome translocation in which 5' sequences of the bcr gene become fused to the c-abl proto-oncogene. The resulting chimeric genes encode bcr/abl fusion proteins which have deregulated tyrosine kinase activity and appear to play an important role in induction of these leukemias. A series of bcr/abl genes were constructed in which nested deletions of the bcr gene were fused to the c-abl gene. The fusion proteins encoded by these genes were assayed for autophosphorylation in vivo and for differences in subcellular localization. Our results demonstrate that bcr sequences activate two functions of c-abl; the tyrosine kinase activity and a previously undescribed microfilament-binding function. Two regions of bcr which activate these functions to different degrees have been mapped: amino acids 1 to 63 were strongly activating and amino acids 64 to 509 were weakly activating. The tyrosine kinase and microfilament-binding functions were not interdependent, as a kinase defective bcr/abl mutant still associated with actin filaments and a bcr/abl mutant lacking actin association still had deregulated kinase activity. Modification of actin filament functions by the bcr/abl tyrosine kinase may be an important event in leukemogenesis.
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PMID:Activation of tyrosinase kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. 170 8

We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL). These patients had either the characteristic Philadelphia chromosome (Ph1) [t(9;22)(q34;q11)] or cytogenetically similar variants with a 22q11 breakpoint but no detectable cytogenetic involvement of 9q34. The findings suggested two distinct subtypes of ALL: one defined by t(9;22)(q34;q11) and expression of P185BCR-ABL tyrosine kinase and one with variant karyotypes and no P185BCR-ABL expression. The former comprises cases with Ph1 + marrow cells and Ph1 + erythroid and (or) myeloid colonies in remission marrow and others in which the t(9;22) is undetectable in remission marrow cells. In the latter subgroup, the disease may reflect more extreme mosaicism with a similar stem cell that is cytogenetically undetectable. Variant karyotypes included a del(22)(q11) in one patient and a t(6;22;15;9) (q21;q11;q?22;q21) in another; in both instances, the malignant blast cells lacked P185BCR-ABL expression. Thus ALL with t(9;22)(q34;q11) should be distinguished from ALL with other involvement of the 22q11 breakpoint by molecular studies including protein expression. The diversity of karyotypic findings in cases with involvement of 22q11 suggests at least two mechanisms of leukemogenesis in patients with ALL defined by this breakpoint.
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PMID:Comparative biochemical and cytogenetic studies of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and other 22q 11 variants. 264 73

The Philadelphia chromosome (Ph) is an abbreviated chromosome number 22 resulting, in the majority of cases, from a balanced translocation between the 9 and 22 long arms. It is considered a marker of chronic myeloid leukemia and its diagnostic and prognostic value in this disease has been demonstrated. It is also present in a number of patients with acute leukemias of poor prognosis. The Ph arises in a bone marrow progenitor cell and seems to allow the clonal expansion of the malignant cells. The typical 9;22 translocation results in the transposition of the cellular oncogene Abelson in close proximity of chromosome 22 linked critical sequences. This structural change leads to the transcription of an hybrid mRNA coding for an abnormal protein with a tyrosine kinase activity which could play a major role in the leukemogenesis process.
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PMID:[The Philadelphia chromosome: clinical and biological significance]. 294 11

Realising the therapeutic potential of colony-stimulating factors (CSFs) depends upon understanding the biological responses elicited by these regulators in target hemopoietic cells, and determining the biochemical nature of signals transduced through their receptors. These signals can lead to growth, differentiation or the activation of an effector function. CSF-dependent cells maintained in culture resemble pre-leukemic cells and releasing cells from a factor-dependent growth state must be a final step in leukemogenesis. The measurement of metabolic changes in cells following ligand-receptor interactions has thus far failed to reveal the biochemical identity of growth signal transducing events. The patterns of growth responses observed in various CSF-dependent cell lines provide some idea of the relationship of these events for different CSF species. A number of IL-3-dependent cell lines can be switched to an IL-2- or a GM-CSF-dependent growth state. This implies the intracellular pathways activated by signal transduction through their different receptors must be related. The expression of the v-src oncogene in IL-3- and GM-CSF-dependent cells leads to CSF-independent growth, whereas in an IL-2-dependent growth state the expression of v-src in these same cells does not lead to a loss of the requirement for IL-2 for growth. It might be argued that signal transduction through IL-3- or GM-CSF-specific receptors involves a protein tyrosine kinase. However, the addition of IL-3 or GM-CSF to cells expressing v-src results in a decrease in tyrosine kinase activity, suggesting that the effect of IL-3- or GM-CSF-specific signal transduction is to inhibit the expression of tyrosine kinase. It is unlikely that G-CSF signal transduction involves a receptor-associated tyrosine kinase. 32Dcl-23 cells respond to G-CSF by cell division and terminal differentiation, but when these cells are transformed to factor-independent growth following v-src infection, they remain responsive to G-CSF but lose the capacity to terminally differentiate. We have investigated the growth and differentiative responses of a range of human myeloid leukemias to G-CSF, IL-3 and GM-CSF. There is heterogeneity in the responses of different leukemic cells to these growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of colony-stimulating factors on leukemia progenitor cells and oncogene expression. 307 33

The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.
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PMID:Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia. 317 49

The deregulated tyrosine kinase activity of the Bcr/Abl protein has been causally linked to the development of Philadelphia (Ph) chromosome-positive leukemia in mice and man. Abnormally tyrosine-phosphorylated substrates of the Bcr/Abl kinase in Ph-positive cells are likely to contribute to leukemogenesis by interfering with normal signal transduction pathways. We have previously shown that the adaptor molecule Crkl is a major in vivo substrate for the Bcr/Abl tyrosine kinase, and it is thought to connect Bcr/Abl with downstream effectors. In the current study, a tyrosine-phosphorylated protein with a molecular mass of approximately 120 kDa was identified which binds only to the Crkl Src homology 2 (SH2) domain in cells, including Ph-positive patient material, containing an active Bcr/Abl protein. We demonstrate here that this protein is Cbl, originally discovered as an oncogene which induces B-cell and myeloid leukemias in mice. The Crkl SH2 domain binds specifically to Cbl. The Src homology 3 (SH3) domains of Crkl do not bind to Cbl, but do bind Bcr/Abl. These findings suggest the existence of a trimolecular complex involving Bcr/Abl, Crkl, and Cbl and are consistent with a model in which Crkl mediates the oncogenic signal of Bcr/Abl to Cbl.
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PMID:Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. 754 63


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